3beta-halo-delta5 and 3-desoxy-delta5 cortical hormones



United States Patent Oflice 3,203,967 Patented Aug. 31, 1965 3,203,9673fl-HAL0-A AND 3-DES0XY-A CORTICAL HORMONES John 'A. Zderic, Palo Alto,Calif., and Otto Halpern and Jose Iriarte, Mexico City, Mexico,assignors, by mesne assignments, to Syntex Corporation, a corporation ofPanama No Drawing. Filed Dec. 26, 1961, Ser. No. 162,231 24 Claims. (Cl.260-39145) CHsOR In the above formula X represents keto or B-hydroxy, Yrepresents chlorine, bromine, fluorine or hydrogen; R may be hydrogen oran acyl group derived from hydrocarbon carboxylic acids containing lessthan 12 carbon atoms which may be saturated or unsaturated, of straight,branched, cyclic or cyclic-aliphatic chain, aromatic and may besubstituted by functional groups such as hydroxy, alkoxy containing upto 5 carbon atoms, acyloxy containing up to 12 carbon atoms, nitro,amino or halogen. Typical ester groups are the acetate, propionate,enanthate, benzoate, trimethylacetate, t-butylacetate, phenoxyacetate,cyclopenthylpropionate, aminoacetate and fl-chloropropionate.

The novel compounds of the present invention are prepared by the processillustrated by the following equation:

CHzOR i=0 r15 ga'm |-IZ HO-- Q I 115:3 if (IV) Z I I (VIII) L0 I Ii- 8110 j HO 0 I Y i 23 o-on,

In the above formulas R 'and Y have the same meaning as set forthhereinbefore and Z represents fluorine, chlorine or bromine.

In practicing the process outlined above A -pregnen-3B,l7og,21-t1iol-l1,20-dione-21-acetate is saponified in a basic mediumsuch as a methanolic solution of potassium hydroxide to give A pregnen3B,17oi,21 triol 11,20- dione. Upon conventional treatment of thislatter compound with formaldehyde in the presence of an acid, as forexample hydrochloric acid, yields the corresponding17,20;20,21-bismethylenedioxy derivative (I). Reaction of this compoundwith ahalogenating agent such as hydrogen fluoride, phosphoruspentachloride or phosphorus pentabromide, in a solvent inert to thereagent, furnishes the corresponding35-halo=17,20;20,2l-bismethylenedioxy- A -pregnen-11-one (II). Thislatter compound is treated with an alkali metal, preferably sodium, inliquid ammonia for a period of time of the order of 5 minutes, givingthe respective 3 desoxy 17,20;20,21-bismethylenedioxy-A -pregnen-11aol(IV). Oxidation of the hydroxy group of the latter compound with asuitable reagent preferably 8 N chromic acid yields the corresponding17,20;20,21 bismethylenedioxy A -pregnen-11-one (VI).

The aforementioned 3-desoxy or 3fl-halo-17,20;20,21-bismethylenedioxy-M-pregnen-1 l-one compounds are reduced, preferablywith sodium borohydride, affording the respective 3 desoxy (V) or 3Bhalo 17,20;20,2I- bismethylenedioxy-A -pregnen-1lfl-ols (VIII).

The hereinbefore obtained SB-halo and 3-desoxy-17;20;20,2l-bismethylenedioxy derivatives (II, V, VI, VIII) uponhydrolysis in an acid medium, preferably 50% acetic acid, at refluxtemperature for a period of time of the order of 25 minutes yield thecorresponding 3 A -pregnen-17a,21 di01-20-one derivatives (HL VII, IX;

R= H). H

These compounds are conventionally acylated in pyrid1ne with anacylating agent as for example acetic anhydnde or propionic anhydride,affording the corresponding 2l-acy1oxy derivatives (I11, VII, IX;R=acyl).

The following specific examples serve to illustrate but are not intendedto limit the scope of the present invention:

Example I Q g. of A -pregnen-3B,l7a,21-triol-11,20-dione-21-acetate[Wall, J. Am. Chem. Soc. 81, 411 (1959)] dissolved in 150 cc. ofmethanol and treated with 15 cc. of a 4% aqueous solution of potassiumhydroxide; the reaction mixture was stirred for 1 hour under anatmosphere of nitrogen at C.; the mixture was neutralized with aceticacid and the methanol distilled under reduced pressure. The residue wastriturated with water and the solid collected, washed with water, driedand recrystallized from ethyl acetate-methanol, thus producing A-pregnen- 3 6, 17,21-tri0l-11,20-dione.

Example 11 A solution of 5 g. of the compound produced in the precedingexample in 40 cc. of 37% aqueous formaldehyde was treated with 0.5 cc.of concentrated hydrochloric acid and the mixture stirred for 48 hoursat room temperature. It was then poured into water, the formedprecipitate filtered off, washed, with water to neutral and dried undervacuum thus affording17,20;20,21-bismethylenedioxy-M-pregnen-afi-ol-1l-one mixed with theB-methylenedioxy derivative thereof.

The foregoing mixture was heated on the steam bath with 200 cc. of 50%acetic acid under nitrogen for 30 minutesyit was then concentrated undervacuum to a small volume and poured into water. The precipitate wascollected, washed well with water, dried and recrystallized fromacetone-hexane, thus furnishing pure 17,20 ;20,2 1-bismethylenedioxy-A-pregnen3 fi-ol-l l-one.

Example Ill To a solution of 5 g. of the latter steroid in 100 cc. ofbenzene were added 5 g. of phosphorus pentachloride and the resultingmixture was refluxed for 1 hour in the absence of moisture. It was thencooled, poured into water; the benzene layer was washed with waterseveral times, dried over anhydrous sodium sulfate and evaporated todryness. Crystallization of the residue from acetone-hexane yielded3B-chloro-17,20;20,21-bismethylenedioxy-A -pregnen- 1 l-one;

Following the same procedure except that phosphorus pentachloride wassubstituted by phosphorus pentabromide Example V A solution of 4 g. of3/3-chloro-17,20;20,21-bismethylenedioxy-A -pregnen-1l-one in 40 cc. oftetrahydrofuran was added in a steady stream to a solution of l g. of ofsodium in 200 cc. of liquid ammonia with good stirring. After 5 minutes,methanol was added dropwise until the blue color was discharged and theammonia was then allowed to evaporate. The resulting mixture wasevaporated to dryness and the residue taken up in benzene. The mixturewas washed with dilute hydrochloric acid, water to neutral, dried overanhydrous sodium sulfate and evaporated to dryness. Crystallization frommethylene chloride-acetone yielded l7,20;20,2l-bismethylenedioxy-M-pregnen-l 106-01.

Example VI A solution of 2 g. of the above product in 20 cc. of acetonewas cooled to 0 C. and treated under an atmosphere of nitrogen and withstirring, with a solution of 8 N chromic acid (prepared by mixing 26 g.of chromium trioxide with 23 cc. of concentrated sulfuric acid anddiluting with water to 100 cc.), until the color of the reagentpersisted in the mixture. It was stirred for 5 minutes further at 05 C.and diluted with water. The precipitate was collected, washed with waterand dried under vacuum, thus alfording a crude product which uponrecrystallization from acetone-hexane gave 17,20;20,21-bismethylenedioxy-A -pregnen-1 l-one.

Example VII A solution of 2 g. of sodium borohydride in 3 cc. of waterwas added to an ice-cooled solution of 2 g. of

' chloro-17,20;20,2l-bismethylenedioxy A pregncne-llthere was obtained3}8-bromo-17,20;20,2l-bismethylenedioxy-A -pregnen-l l-one.

Example IV ture lower than 10 C. for 6 additional hours, thenneutralized by cautiously adding a 5% aqueous sodium bicarbonatesolution and transferred to a separatory funover anhydrous sodiumsulfate and concentrated until .formation of an abundant precipitate.The mixture was cooled, the precipitate filtered and redissolved in hotethyl acetate, the insoluble material was filtered off and the filtratecooled whereby there crystallized Zip-fluoro- 17,20;20,21-bismethylenedioxy-A -pregnen-1 l-one.

.nel. The organic layer was washed with water, dried one, in 220 cc. ofmethanol and the mixture was allowed to stand for 16 hours at roomtemperature. The excess reagent was decomposed by addition of aceticacid, the solution concentrated to small volume in vacuo and dilutedwith water. The product was extracted with ethyl acetate, the extractwas washed with water, dried and evaporated. The solid residue waspurified by crystallization from acetone-hexane to give3fi-chloro-17,20;20,21- bismethylenedioxy-A pregnen-1 1 fi-ol.

Following the same technique, there were reduced 17,20;20,21-bismethylenedioxy-M-pregnen-1 l-one,318-bromo-17,20;20,21-bismethylenedioxy-A -pregnenll-one andSB-fluoro-17,20;20,21-bismethylenedioxy-M-pregnenll-one, thus giving17,20;20,21-bismethylenedioxy-A -pregnene-1 lfi-ol, 3flbromo-17,20;20,21-bismethylenedioxy-A -pregnenellfl-ol and3,8-fluoro-17,20;20,2l-bismethylenedioxy-A -pregnen- Example VII ExampleIX A mixture of 1 g. of 3p-chIoro-A -pregnen-17a,21-diol- 11,20-dione, 4cc. of pyridine and 2 cc. of acetic anhydride was kept at roomtemperature overnight, poured into ice water, the formed precipitate wasfiltered, washed with water and dried. Crystallization fromacetone-hexane gave 3fi-chloro-A -pregnen-170:,2l-cliol 11,20 dione-21-acetate.

By the same technique were treated A -pregnen-l 1fi,17a-triol-20-one,

A -pregnen-17a,21-diol-1 1,20-dione,

3 fi-chloro-M-pregnen-l 1,6, 17a,21-trio1-20-one,

3 fi-bromo-A -pregnen- 1 1 B, 17,2 1-triol-20-one,

3fi-bromo-A -pregnen-17a,21-diol-1 1,20-dione,

3B-fluoro-A -pregnen-17u,21-dio1-11,20-dione and 3 fi-fluoro-A pregnen-l118, 17u,21-triol-20-one affording correspondingly A -pregnen-11fi,17a,21-t1iol-20-one-2 l-acetate,

A -pregnen-l7a,21-dioll 1,20-dione-21-acetate,

3 B-chloro-A -pregnen-1 1B,17a,21-triol-20-one- 2l-acetate,

3 ,B-bromo-M-pregnen- 1 1fl,17,21-trio1-20-one- 21-acetate,

3 fl-bromo-A pregnen-17oc,2 l-diol-l 1,20-dione- 2l-acetate,3fi-fluoro-A -pregnen-17a,21-diol-1 1,20-dione- 21-acetate,

3 ,B-fluoro-M-pregnen- 1 1,8, 17a,20-triol-20-one- ZI-acetate.

Example X Following the technique described in the foregoing exampleexcept that acetic anhydride was substituted by propionic anhydride,caproic anhydride, cyclopentylpropionic anhydride and benzoyl chloride,there were correspondingly obtained the 21-propionates, 21-caproates,21- cyclopentylpropionates and 21-benzoates of the starting compoundsnamed in the same example.

We claim:

1. A compound of the following formula:

CHaOR a? CU wherein X is a member of the group consisting of keto andB-hydroxy, Y is selected from the group consisting of hydrogen,fluorine, chlorine and bromine and R is a member of the group consistingof hydrogen and a hydrocarbon carboxylic acyl group of less than 12carbon atoms.

i A compound of the formula:

CH OH e .Ql

wherein X is a member of the group consisting of keto and fi-hydroxy.

. A -pregnen-11fi,17a,21-triol-20-one.

. 3fl-chloro-A -pregnene-11/3,17a,2l-triol-20-one.

. 3B-chloro-A -pregnen-170:,21-di01-11,20-dione.

A -pregnen-17a,21-diol-1 1,20-dione.

. 3 fi-bromo-M-pregnen-17a,21-diol-11,20-dione.

10. 3fi-fluoro-A -pregnen-17a,21-diol-11,20-dione.

11. The 21-esters of hydrocarbon carboxylic acids of less than 12 carbonatoms of A -pregnen-11 8,17a,2l-triol- 20-one.

12. The 21-esters of hydrocarbon carboxylic acids of less than 12 carbonatoms of 3fi-chloro-A -pregnen-11B, 17a,21-tIiO1-20-0I16.

13. The 21-esters of hydrocarbon carboxylic acids of less than 12 carbonatoms of 3fl-chloro-A -pregnen-17a, 21-diol-1 1,20-dione.

14. The 2l-esters of hydrocarbon carboxylic acids of less than 12 carbonatoms of A -pregnen-17a,21-diol-11, 20-dione.

15. The 21-esters of hydrocarbon carboxylic acids of less than 12.carbon atoms of 3B-bromo-A pregnen-17a, 21-diol-1 1,20-dione.

16. The 21-esters of hydrocarbon carboxylic acids of less than 12 carbonatoms of BB-bromo-M-pregnemllfi,

17a,21-triol-20-one.

17. The 21-esters of hydrocarbon carboxylic acids of less than 12 carbonatoms of 3fi-fluoro-A -pregnen-llfl, 17,2l-triol-20-one.

18. The 21-esters of hydrocarbon carboxylic acids of less than 12 carbonatoms of 3fl-fluoro-A -pregnen-l7u, 21-diol-11,20-dione.

19. A method for the production of 3fl-halo-A-pregnen-17a,21-dio1-11,20-dione compounds which comprises treating17,20;20,21 bismethylenedioxy-A -pregnen-3 [3-01- ll-one with ahalogenating agent in an inert solvent and hydrolyzing the obtained3,8-halo-17,20;20,2l-bismethylenedi0Xy-A -pregnen-1l-one derivative inan acid medium.

20. The method of claim 19 wherein the halogenating agent is phosphorouspentachloride, the solvent is benzene and the acid medium is 50% aceticacid.

21. The method of claim 19 wherein the halogenating agent is phosphoruspentabromide, the solvent is benzene and the acid medium is 5 0% aceticacid.

22. The method of claim 19 wherein the halogenating agent is hydrogenfluoride, the solvent is a mixture of methylene chloride andtetrahydrofuran, and the acid medium is 50% acetic acid.

23. The method for the production of A -pregnen-11B, 17u,21-trio1-20-onewhich comprises treating a 3/3-halo- 17,20;20,21 bismethylenedioxy-A-pregnen-l l-one compound with an alkali metal in ammonia, oxidizing theproduced 17,20;20,2l-bismethylenedioxy-A -pregnen 11aol with chromicacid, reducing the resulting 17,20;20,21- bismethylenedioxy Apregnene-ll-one with a double 7 metalhydride, and hydrolyzing theobtained 17,20;20,21- bismethylenedioxy-M-pregnen-1lfi ol in an acidmedium. 24. The method of claim 23 wherein the alkali metal is sodium,the chromic acid is 8 N, the double metalhydride is sodium borohydrideand the acid medium is 50% acetic acid.

No'references cited.

MORRIS LIEBMAN, Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3 203,967 August 31, 1965 John A. Zderic et al It is hereby certified thaterror appears in the above numbered patent requiring correction and thatthe said Letters Patent should read as corrected below.

Column 1 lines 20 to 30 the formula should appear as shown below insteadof as in the patent:

CH OR same column 1 lines 60 to 70, formula "II" should appear as shownbelow instead of as in the patent:

Signed and sealed this 5th day of April 1966.

(SEAL) Attest:

ERNESEW. SWIIJER EDWARD J. BRENNER Attestlng Officer Commissioner ofPatents

1. A COMPOUND OF THE FOLLOWING FORMULA: